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The Comparative Toxicogenomics Database (CTD; http://ctdbase.org/) provides information about interactions between environmental chemicals and gene products and their relationships to diseases. Chemical–gene, chemical–disease and gene–disease interactions manually curated from the literature are integrated to generate expanded networks and predict many novel associations between different data types. CTD now contains over 15 million toxicogenomic relationships. To navigate this sea of data, we added several new features, including DiseaseComps (which finds comparable diseases that share toxicogenomic profiles), statistical scoring for inferred gene–disease and pathway–chemical relationships, filtering options for several tools to refine user analysis and our new Gene Set Enricher (which provides biological annotations that are enriched for gene sets). To improve data visualization, we added a Cytoscape Web view to our ChemComps feature, included color-coded interactions and created a ‘slim list’ for our MEDIC disease vocabulary (allowing diseases to be grouped for meta-analysis, visualization and better data management). CTD continues to promote interoperability with external databases by providing content and cross-links to their sites. Together, this wealth of expanded chemical–gene–disease data, combined with novel ways to analyze and view content, continues to help users generate testable hypotheses about the molecular mechanisms of environmental diseases.

Herpes simplex virus (HSV) recombinants induce durable immune responses in rhesus macaques and mice and have induced partial protection in rhesus macaques against mucosal challenge with virulent simian immunodeficiency virus (SIV). In this study, we evaluated the properties of a new generation HSV vaccine vector, an HSV-1 multiple immediate-early (IE) gene deletion mutant virus, d106, which contains deletions in the ICP4, ICP27, ICP22, and ICP47 genes. Because several of the HSV IE genes have been implicated in immune evasion, inactivation of the genes encoding these proteins was expected to result in enhanced immunogenicity. The d106 virus expresses few HSV gene products and shows minimal cytopathic effect in cultured cells. When d106 was inoculated into mice, viral DNA accumulated at high levels in draining lymph nodes, consistent with an ability to transduce dendritic cells and activate their maturation and movement to lymph nodes. A d106 recombinant expressing Escherichia coli beta-galactosidase induced durable beta-gal-specific IgG and CD8(+) T cell responses in naive and HSV-immune mice. Finally, d106-based recombinants have been constructed that express simian immunodeficiency virus (SIV) gag, env, or a rev-tat-nef fusion protein for several days in cultured cells. Thus, d106 shows many of the properties desirable in a vaccine vector: limited expression of HSV gene products and cytopathogenicity, high level expression of transgenes, ability to induce durable immune responses, and an ability to transduce dendritic cells and induce their maturation and migration to lymph nodes.

The Comparative Toxicogenomics Database (CTD) is a public resource that promotes understanding about the interaction of environmental chemicals with gene products, and their effects on human health. Biocurators at CTD manually curate a triad of chemical-gene, chemical-disease and gene-disease relationships from the literature. These core data are then integrated to construct chemical-gene-disease networks and to predict many novel relationships using different types of associated data. Since 2009, we dramatically increased the content of CTD to 1.4 million chemical-gene-disease data points and added many features, statistical analyses and analytical tools, including GeneComps and ChemComps (to find comparable genes and chemicals that share toxicogenomic profiles), enriched Gene Ontology terms associated with chemicals, statistically ranked chemical-disease inferences, Venn diagram tools to discover overlapping and unique attributes of any set of chemicals, genes or disease, and enhanced gene pathway data content, among other features. Together, this wealth of expanded chemical-gene-disease data continues to help users generate testable hypotheses about the molecular mechanisms of environmental diseases. CTD is freely available at http://ctd.mdibl.org.

UNLABELLED The Comparative Toxicogenomics Database is a public resource that promotes understanding about the effects of environmental chemicals on human health. Currently, CTD describes over 184,000 molecular interactions for more than 5,100 chemicals and 16,300 genes/proteins. We have leveraged this dataset of chemical-gene relationships to compute similarity indices following the statistical method of the Jaccard index. These scores are used to produce lists of comparable genes ("GeneComps") or chemicals ("ChemComps") based on shared toxicogenomic profiles. GeneComps and ChemComps are now provided for every curated gene and chemical in CTD. ChemComps are particularly significant because they provide a way to group chemicals based upon their biological effects, instead of their physical or structural properties. These metrics provide a novel way to view and classify genes and chemicals and will help advance testable hypotheses about environmental chemical-genedisease networks. AVAILABILITY CTD is freely available at http://ctd.mdibl.org/

Background Pathogenesis of complex diseases involves the integration of genetic and environmental factors over time, making it particularly difficult to tease apart relationships between phenotype, genotype, and environmental factors using traditional experimental approaches. Results Using gene-centered databases, we have developed a network of complex diseases and environmental factors through the identification of key molecular pathways associated with both genetic and environmental contributions. Comparison with known chemical disease relationships and analysis of transcriptional regulation from gene expression datasets for several environmental factors and phenotypes clustered in a metabolic syndrome and neuropsychiatric subnetwork supports our network hypotheses. This analysis identifies natural and synthetic retinoids, antipsychotic medications, Omega 3 fatty acids, and pyrethroid pesticides as potential environmental modulators of metabolic syndrome phenotypes through PPAR and adipocytokine signaling and organophosphate pesticides as potential environmental modulators of neuropsychiatric phenotypes. Conclusion Identification of key regulatory pathways that integrate genetic and environmental modulators define disease associated targets that will allow for efficient screening of large numbers of environmental factors, screening that could set priorities for further research and guide public health decisions.

Background The etiology of many chronic diseases involves interactions between environmental factors and genes that modulate physiological processes. Understanding interactions between environmental chemicals and genes/proteins may provide insights into the mechanisms of chemical actions, disease susceptibility, toxicity, and therapeutic drug interactions. The Comparative Toxicogenomics Database (CTD; http://ctd.mdibl.org) provides these insights by curating and integrating data describing relationships between chemicals, genes/proteins, and human diseases. To illustrate the scope and application of CTD, we present an analysis of curated data for the chemical arsenic. Arsenic represents a major global environmental health threat and is associated with many diseases. The mechanisms by which arsenic modulates these diseases are not well understood. Methods Curated interactions between arsenic compounds and genes were downloaded using export and batch query tools at CTD. The list of genes was analyzed for molecular interactions, Gene Ontology (GO) terms, KEGG pathway annotations, and inferred disease relationships. Results CTD contains curated data from the published literature describing 2,738 molecular interactions between 21 different arsenic compounds and 1,456 genes and proteins. Analysis of these genes and proteins provide insight into the biological functions and molecular networks that are affected by exposure to arsenic, including stress response, apoptosis, cell cycle, and specific protein signaling pathways. Integrating arsenic-gene data with gene-disease data yields a list of diseases that may be associated with arsenic exposure and genes that may explain this association. Conclusion CTD data integration and curation strategies yield insight into the actions of environmental chemicals and provide a basis for developing hypotheses about the molecular mechanisms underlying the etiology of environmental diseases. While many reports describe the molecular response to arsenic, CTD integrates these data with additional curated data sets that facilitate construction of chemical-gene-disease networks and provide the groundwork for investigating the molecular basis of arsenic-associated diseases or toxicity. The analysis reported here is extensible to any environmental chemical or therapeutic drug.

The Comparative Toxicogenomics Database (CTD) is a curated database that promotes understanding about the effects of environmental chemicals on human health. Biocurators at CTD manually curate chemical–gene interactions, chemical–disease relationships and gene–disease relationships from the literature. This strategy allows data to be integrated to construct chemical–gene–disease networks. CTD is unique in numerous respects: curation focuses on environmental chemicals; interactions are manually curated; interactions are constructed using controlled vocabularies and hierarchies; additional gene attributes (such as Gene Ontology, taxonomy and KEGG pathways) are integrated; data can be viewed from the perspective of a chemical, gene or disease; results and batch queries can be downloaded and saved; and most importantly, CTD acts as both a knowledgebase (by reporting data) and a discovery tool (by generating novel inferences). Over 116 000 interactions between 3900 chemicals and 13 300 genes have been curated from 270 species, and 5900 gene–disease and 2500 chemical–disease direct relationships have been captured. By integrating these data, 350 000 gene–disease relationships and 77 000 chemical–disease relationships can be inferred. This wealth of chemical–gene–disease information yields testable hypotheses for understanding the effects of environmental chemicals on human health. CTD is freely available at http://ctd.mdibl.org.

The Comparative Toxicogenomics Database (CTD; http://ctdbase.org/) is a public resource that curates interactions between environmental chemicals and gene products, and their relationships to diseases, as a means of understanding the effects of environmental chemicals on human health. CTD provides a triad of core information in the form of chemical-gene, chemical-disease, and gene-disease interactions that are manually curated from scientific articles. To increase the efficiency, productivity, and data coverage of manual curation, we have leveraged text mining to help rank and prioritize the triaged literature. Here, we describe our text-mining process that computes and assigns each article a document relevancy score (DRS), wherein a high DRS suggests that an article is more likely to be relevant for curation at CTD. We evaluated our process by first text mining a corpus of 14,904 articles triaged for seven heavy metals (cadmium, cobalt, copper, lead, manganese, mercury, and nickel). Based upon initial analysis, a representative subset corpus of 3,583 articles was then selected from the 14,094 articles and sent to five CTD biocurators for review. The resulting curation of these 3,583 articles was analyzed for a variety of parameters, including article relevancy, novel data content, interaction yield rate, mean average precision, and biological and toxicological interpretability. We show that for all measured parameters, the DRS is an effective indicator for scoring and improving the ranking of literature for the curation of chemical-gene-disease information at CTD. Here, we demonstrate how fully incorporating text mining-based DRS scoring into our curation pipeline enhances manual curation by prioritizing more relevant articles, thereby increasing data content, productivity, and efficiency.

The Comparative Toxicogenomics Database (CTD) is a public resource that promotes understanding about the effects of environmental chemicals on human health. CTD biocurators read the scientific literature and convert free-text information into a structured format using official nomenclature, integrating third party controlled vocabularies for chemicals, genes, diseases and organisms, and a novel controlled vocabulary for molecular interactions. Manual curation produces a robust, richly annotated dataset of highly accurate and detailed information. Currently, CTD describes over 349,000 molecular interactions between 6800 chemicals, 20,900 genes (for 330 organisms) and 4300 diseases that have been manually curated from over 25,400 peer-reviewed articles. This manually curated data are further integrated with other third party data (e.g. Gene Ontology, KEGG and Reactome annotations) to generate a wealth of toxicogenomic relationships. Here, we describe our approach to manual curation that uses a powerful and efficient paradigm involving mnemonic codes. This strategy allows biocurators to quickly capture detailed information from articles by generating simple statements using codes to represent the relationships between data types. The paradigm is versatile, expandable, and able to accommodate new data challenges that arise. We have incorporated this strategy into a web-based curation tool to further increase efficiency and productivity, implement quality control in real-time and accommodate biocurators working remotely. Database URL: http://ctd.mdibl.org.